(Adapted from application): The ultimate goal of this research program is to develop methods for structure-based drug design, with an emphasis on aiming at new targets for the treatment of AIDS. New strategies will be taken toward obtaining structural information about the envelope glycoprotein (gp120/gp41), which, despite considerable efforts, has yet to yield to detailed structural determination. To develop strategies for targeting RNA elements, the new structures of TAR and RRE will be used as the basis for ligand discovery. The structures of HIV-derived peptides, complexed with class II MHC proteins, will be determined and used to guide the design of synthetic T-cell antigens. Methods for determining structures at high resolution (X-ray crystallography, NMR spectroscopy) will be used in these studies. A major hurdle in the translation of such structure into new therapies is the lack of effective, reproducible and generalizable approaches for the design of lead compounds. Therefore, a key aim of the proposed program is to develop new computational methodologies for structure-based drug design. Free-energy based models, with a particular emphasis on electrostatic interactions, will be developed. Two steps will be taken to ensure that there is rapid and plentiful experimental feedback for testing these computational methods. First, the computational methods will be applied to targets that are being investigated experimentally within the program. Second, the program will utilize well-established combinatorial synthesis methods to assist identification of ligands, so that experimental evaluation of the computational methods is facilitated.